Abstract This planning grant will conduct statistical simulations and logistical planning for a multicenter, dose-finding, five-arm, blinded, placebo controlled, adaptive design trial that has been planned in conjunction with the Clinical and Data Coordination Centers of the NIH-funded national Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN). The disease of study is pulmonary embolism (PE), which is the fourth leading cause of cardiovascular death in the US. Administration of a clot-dissolving fibrinolytic enzyme in addition to standard care anticoagulation to patients with acute PE causes faster and more complete removal of clot. However, the risks and benefits of adjunctive fibrinolytic treatment for normotensive patients remain poorly defined because of small numbers and heterogeneity of existing trials. The only fibrinolytic agent approved for use in PE by the FDA is alteplase at a 100 mg dose. A large body of literature indicates that bleeding from alteplase is dose-dependent. Five randomized trials (with two treatment arms in each) have suggested equal benefit and lower bleeding risk with 50 mg of alteplase (half dose). No study has simultaneously compared multiple doses of alteplase to determine the lowest effective dose, and therefore, most likely, also the safest dose. The adaptive design will allow the most efficient determination of the optimal dose. Death as an endpoint poses several problems, including difficulty with assigning cause, low frequency (2-3%), and the availability of a predictor of death. Instead, we plan to use RV function, defined by echocardiography and troponin measurements as the primary outcome because both measurements normal indicate low risk of deterioration. The secondary outcome assesses exercise capacity at 6 months, including measurements from cardiopulmonary exercise testing (CPET). Aim 1 of this planning grant will conduct simulations to inform the final trial design, based on relevant adaptive design parameters. Sample size, update frequency, and the responsive adaptive randomization scheme will be evaluated in order to optimize key operating characteristics including likelihood of identifying the correct dose of alteplase (chosen from 0, 25, 50, 75 and 100 mg) and surpassing the Go, NoGo criteria. Aim 2 will conduct extensive survey of potential sites for their ability to enroll adequate numbers and execute all study procedures, and will allow construction of the steering committee, the final protocol, guidance document and manual of procedures. This planning grant will facilitate the execution of an innovative but complex trial designed to fill a major gap in current care of patients with PE.